Thermosensitive hydrogel with emodin-loaded triple-targeted nanoparticles for a rectal drug delivery system in the treatment of chronic non-bacterial prostatitis.
Journal of nanobiotechnology
BACKGROUND:The complex etiology and pathogenesis underlying Chronic Non-Bacterial Prostatitis (CNP), coupled with the existence of a Blood Prostate Barrier (BPB), contribute to a lack of specificity and poor penetration of most drugs. Emodin (EMO), a potential natural compound for CNP treatment, exhibits commendable anti-inflammatory, anti-oxidant, and anti-fibrosis properties but suffers from the same problems as other drugs. METHODS:By exploiting the recognition properties of lactoferrin (LF) receptors that target intestinal epithelial cells (NCM-460) and prostate epithelial cells (RWPE-1), a pathway is established for the transrectal absorption of EMO to effectively reach the prostate. Additionally, hyaluronic acid (HA) is employed, recognizing CD44 receptors which target macrophages within the inflamed prostate. This interaction facilitates the intraprostatic delivery of EMO, leading to its pronounced anti-inflammatory effects. A thermosensitive hydrogel (CS-Gel) prepared from chitosan (CS) and β-glycerophosphate disodium salt (β-GP) was used for rectal drug delivery with strong adhesion to achieve effective drug retention and sustained slow release. Thus, we developed a triple-targeted nanoparticle (NPs)/thermosensitive hydrogel (Gel) rectal drug delivery system. In this process, LF, with its positive charge, was utilized to load EMO through dialysis, producing LF@EMO-NPs. Subsequently, HA was employed to encapsulate EMO-loaded LF nanoparticles via electrostatic adsorption, yielding HA/LF@EMO-NPs. Finally, HA/LF@EMO-NPs lyophilized powder was added to CS-Gel (HA/LF@EMO-NPs Gel). RESULTS:Cellular assays indicated that NCM-460 and RWPE-1 cells showed high uptake of both LF@EMO-NPs and HA/LF@EMO-NPs, while Raw 264.7 cells exhibited substantial uptake of HA/LF@EMO-NPs. For LPS-induced Raw 264.7 cells, HA/LF@EMO-NPs can reduce the inflammatory responses by modulating TLR4/NF-κB signaling pathways. Tissue imaging corroborated the capacity of HA/LF-modified formulations to breach the BPB, accumulating within the gland's lumen. Animal experiments showed that rectal administration of HA/LF@EMO-NPs Gel significantly reduced inflammatory cytokine expression, oxidative stress levels and fibrosis in the CNP rats, in addition to exerting anti-inflammatory effects by inhibiting the NF-κB signaling pathway without obvious toxicity. CONCLUSION:This triple-targeted NPs/Gel rectal delivery system with slow-release anti-inflammatory, anti-oxidant, and anti-fibrosis properties shows great potential for the effective treatment of CNP.
10.1186/s12951-023-02282-7
NIR-II Responsive Nanohybrids Incorporating Thermosensitive Hydrogel as Sprayable Dressing for Multidrug-Resistant-Bacteria Infected Wound Management.
ACS nano
Developing an effective dressing against bacterial infection and synchronously addressing wound complications, such as bleeding, long-term inflammation, and reinfection, are highly desirable in clinical practice. In this work, a second near-infrared (NIR-II) responsive nanohybrid consisting of mipenem encapsulated iposome with old-shell and lipopolysaccharide (LPS)-targeting ptamer, namely , is constructed for bacteria elimination. Benefiting from the delicate structure, exhibits strong affinity and a reliable photothermal/antibiotic therapeutic effect toward multidrug-resistant (). Furthermore, by incorporating with a thermosensitive hydrogel poly(lactic--glycolic acid)-polyethylene glycol-poly(lactic--glycolic acid) (PLGA-PEG-PLGA), a sprayable dressing was prepared, which enables a quick on-demand gelation (10 s) for wound hemostasis and offers excellent photothermal/antibiotic efficacy to sterilize the infected wound. Additionally, provides satisfactory wound-healing environments by reeducating wound-associated macrophages for inflammation alleviation and forming a gel layer to block exogenous bacterial reinfection. This biomimetic hydrogel reveals excellent bacteria eradication and wound recovery effectiveness, demonstrating its promising potential for managing complicated infected wounds.
10.1021/acsnano.2c10742
Regulated extravascular microenvironment reversible thermosensitive hydrogel for inhibiting calcium influx and vasospasm.
Bioactive materials
Arterial vasospasm after microsurgery can cause severe obstruction of blood flow manifested as low tissue temperature, leading to tissue necrosis. The timely discovery and synchronized treatment become pivotal. In this study, a reversible, intelligent, responsive thermosensitive hydrogel system is constructed employing both the gel-sol transition and the sol-gel transition. The "reversible thermosensitive (RTS)" hydrogel loaded with verapamil hydrochloride is designed to dynamically and continuously regulate the extravascular microenvironment by inhibiting extracellular calcium influx. After accurate implantation and following in situ gelation, the RTS hydrogel reverses to the sol state causing massive drug release to inhibit vasospasm when the tissue temperature drops to the predetermined transition temperature. Subsequent restoration of the blood supply alleviates further tissue injury. Before the temperature drops, the RTS hydrogel maintains the gel state as a sustained-release reservoir to prevent vasospasm. The inhibition of calcium influx and vasospasm and is demonstrated using vascular smooth muscle cells, mice mesenteric arterial rings, and vascular ultrasonic Doppler detection. Subsequent animal experiments demonstrate that RTS hydrogel can promote tissue survival and alleviate tissue injury responding to temperature change. Therefore, this RTS hydrogel holds therapeutic potential for diseases requiring timely detection of temperature change.
10.1016/j.bioactmat.2022.08.024
An Injectable Thermosensitive Hydrogel Containing Resveratrol and Dexamethasone-Loaded Carbonated Hydroxyapatite Microspheres for the Regeneration of Osteoporotic Bone Defects.
Small methods
Bone defects in osteoporosis usually present excessive reactive oxygen species (ROS), abnormal inflammation levels, irregular shapes and impaired bone regeneration ability; therefore, osteoporotic bone defects are difficult to repair. In this study, an injectable thermosensitive hydrogel poly (D, L-lactide)-poly (ethylene glycol)- poly (D, L-lactide) (PLEL) system containing resveratrol (Res) and dexamethasone (DEX) is designed to create a microenvironment conducive to osteogenesis in osteoporotic bone defects. This PLEL hydrogel is injected and filled irregular defect areas and achieving a rapid sol-gel transition in situ. Res has a strong anti-inflammatory effects that can effectively remove excess free radicals at the damaged site, guide macrophage polarization to the M2 phenotype, and regulate immune responses. Additionally, DEX can promote osteogenic differentiation. In vitro experiments showed that the hydrogel effectively promoted osteogenic differentiation of mesenchymal stem cells, removed excess intracellular ROS, and regulated macrophage polarization to reduce inflammatory responses. In vivo experiments showed that the hydrogel promoted osteoporotic bone defect regeneration and modulated immune responses. Overall, this study confirmed that the hydrogel can treat osteoporotic bone defects by synergistically modulating bone damage microenvironment, alleviating inflammatory responses, and promoting osteogenesis; thus, it represents a promising drug delivery strategy to repair osteoporotic bone defects.
10.1002/smtd.202300843
Thermosensitive injectable dual drug-loaded chitosan-based hybrid hydrogel for treatment of orthopedic implant infections.
Carbohydrate polymers
A myriad of therapeutic agents and drug delivery systems are available to the surgeons for treating orthopedic implant-associated infections (OIAI), but only very few have demonstrated their effectiveness in preventing bacteria colonization and biofilm formation due to challenges in the local and sustainable therapeutic release. To address this issue, in this work, a thermosensitive injectable hydrogel based on chitosan (CH)-integrated hydroxyapatite nanoparticles (HAP NPs) containing vancomycin (Van) and quercetin (QC)-loaded in F127 micelles (CH-HAP-FQ-Van hydrogel) was fabricated with potential application in the treatment of OIAI. This dual drug delivery system demonstrated a pH-sensitive drug release pattern. In addition, 100 % growth inhibition of Staphylococcus aureus for a duration of 14 days was observed. Apart from the strong antioxidant activities owing to the co-administration of QC even after 432 h, this composite hydrogel revealed 95.88 ± 2.8 % S. aureus biofilm eradication. By consideration of degradation stability (53.52 ± 4.24 %) during 60 days along with smart gelation within 10 min at 37 °C and easy injectability, CH-HAP-FQ-Van hydrogel could be used as a promising ideal local drug delivery system for implant-related infections.
10.1016/j.carbpol.2023.121138
Photodynamic Alginate Zn-MOF Thermosensitive Hydrogel for Accelerated Healing of Infected Wounds.
ACS applied materials & interfaces
Antibiotic resistance reduces the effectiveness of infected wound healing, and it is necessary to develop a new strategy to promote infected wound healing without using antibiotics. Here, we develop a Chlorin e6 (Ce6)-loaded zinc-metal-organic framework (MOF) thermosensitive hydrogel (Ce6@MOF-Gel) based on alginate and poly(propylene glycol) 407, which enhances antibacterial effects and promotes infected wound healing by a novel strategy of combining zinc-MOF with photodynamic therapy (PDT). Zinc-MOF can realize acid-responsive release of Ce6 and improve antibacterial performance without drug resistance by destroying the integrity of bacterial cell membranes and enhancing the production of bacterial reactive oxygen species (ROS). Additionally, Ce6@MOF-Gel enhances the stability, solubility, and photodynamic properties of Ce6. More importantly, Ce6@MOF-Gel reduces inflammation and promotes collagen deposition and re-epithelialization to facilitate infected wound healing. Collectively, the photodynamic MOF-based hydrogel provides a new, efficient, and safe way for accelerated healing of infected wounds.
10.1021/acsami.2c23321
Enhanced diabetic foot ulcer treatment with a chitosan-based thermosensitive hydrogel loaded self-assembled multi-functional nanoparticles for antibacterial and angiogenic effects.
Carbohydrate polymers
Inhibiting bacterial growth and promoting angiogenesis are essential for enhancing wound healing in diabetic patients. Excessive oxidative stress at the wound site can also lead to an accumulation of reactive oxygen species. To address these challenges, a smart thermosensitive hydrogel loaded with therapeutic agents was developed. This formulation features self-assembled nanoparticles named CIZ, consisting of chlorogenic acid (CA), indocyanine green (ICG), and zinc ions (Zn). These nanoparticles are loaded into a chitosan-β-glycerophosphate hydrogel, named CIZ@G, which enables rapid gel formation under photothermal effects. The hydrogel demonstrates good biocompatibility and effectively releases drugs into diabetic foot ulcers (DFU) wound. Benefiting from the dual actions of CA and zinc ions, the hydrogel exhibits potent antioxidative and anti-inflammatory effects, enhances the expression of vascular endothelial growth factor (VEGF) and Platelet endothelial cell adhesion molecule-1 (CD31), and promotes angiogenesis. Both in vitro and in vivo experiments confirm that CIZ@G can effectively inhibit the growth of Staphylococcus aureus post-laser irradiation and accelerate wound remodeling within 14 days. This approach offers a new strategy for the treatment of diabetic foot ulcers (DFU), potentially transforming patient care in this challenging clinical area.
10.1016/j.carbpol.2024.122740
Herbal Products-Powered Thermosensitive Hydrogel with Phototherapy and Microenvironment Reconstruction for Accelerating Multidrug-Resistant Bacteria-Infected Wound Healing.
Advanced healthcare materials
Wound healing and infection remain significant challenges due to the ineffectiveness against multidrug-resistant (MDR) bacteria and the complex oxidative wound microenvironments. To address these issues, thymoquinone-reinforced injectable and thermosensitive TQ@PEG-PAF-Cur hydrogels with dual functions of microenvironment reshaping and photodynamic therapy are developed. The hydrogel comprises natural compound thymoquinone (TQ) and poly (ethylene glycol)-block-poly (alanine-co-phenyl alanine) copolymers (PEG-PAF) conjugated with natural photosensitizer curcumin (Cur). The incorporation of TQ and Cur reduces the sol-to-gel transition temperature of TQ@PEG-PAF-Cur to 30°C, compared to PEG-PAF hydrogel (37°C), due to the formation of strong hydrogen bonding, matching the wound microenvironment temperature. Under blue light excitation, TQ@PEG-PAF-Cur generates significant amounts of reactive oxygen species such as HO, 1O, and ·OH, exhibiting rapid and efficient bactericidal capacities against methicillin-resistant Staphylococcus aureus and broad spectrum β-lactamases Escherichia coli via photodynamic therapy (PDT). Additionally, Cur effectively inhibits the expressions of proinflammatory cytokines in skin tissue-forming cells. As a result, the composite hydrogel can rapidly transform into a gel to cover the wound, reshape the wound microenvironment, and accelerate wound healing in vivo. This collaborative antibacterial strategy provides valuable insights to guide the development of multifunctional materials for efficient wound healing.
10.1002/adhm.202400049
Injectable and Thermosensitive Hydrogel with Platelet-Rich Plasma for Enhanced Biotherapy of Skin Wound Healing.
Advanced healthcare materials
The rapid and effective healing of skin wounds resulted from severe injuries and full-layer skin defects remains a pressing clinical challenge in contemporary medical practice. The reduction of wound infection and rapid healing is helpful to rebuild and repair skin tissue. Here, a thermosensitive chitosan-based wound dressing hydrogel incorporating β-glycerophosphate (GP), hydroxy propyl cellulose (HPC), graphene oxide (GO), and platelet-rich plasma (PRP) is developed, which exhibits the dual functions of antibacterial properties and repair promotion. GP and HPC enhance the mechanical properties through forming hydrogen bonding connection, while GO produces local heat under near-infrared light, leading to improved blood circulation and skin recovery. Notably, antibacterial properties against Pseudomonas aeruginosa, and control-release of growth factors from PRP are also achieved based on the system. In vitro experiments reveal its biocompatibility, and ability to promote cell proliferation and migration. Animal experiments demonstrate that the epithelial repair and collagen deposition can be promoted during skin wound healing in Sprague Dawley rats. Moreover, a reduction in wound inflammation levels and the improvement of wound microenvironment are observed, collectively fostering effective wound healing. Therefore, the composite hydrogel system incorporated with GO and PRP can be a promising dressing for the treatment of skin wounds.
10.1002/adhm.202303930
A Thermosensitive Bi-Adjuvant Hydrogel Triggers Epitope Spreading to Promote the Anti-Tumor Efficacy of Frameshift Neoantigens.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
Tumor-specific frameshift mutations encoding peptides (FSPs) are highly immunogenic neoantigens for personalized cancer immunotherapy, while their clinical efficacy is limited by immunosuppressive tumor microenvironment (TME) and self-tolerance. Here, a thermosensitive hydrogel (FSP-RZ-BPH) delivering dual adjuvants R848 (TLR7/8 agonist) + Zn (cGAS-STING agonist) is designed to promote the efficacy of FSPs on murine forestomach cancer (MFC). After peritumoral injection, FSP-RZ-BPH behaves as pH-responsive sustained drug release at sites near the tumor to effectively transform the immunosuppressive TME into an inflammatory type. FSP-RZ-BPH orchestrates innate and adaptive immunity to activate dendritic cells in tumor-draining lymph nodes and increase the number of FSPs-reactive effector memory T cells (T) in tumor by 2.9 folds. More importantly, these T also exhibit memory responses to nonvaccinated neoantigens on MFC. This epitope spreading effect contributes to reduce self-tolerance to maintain long-lasting anti-tumor immunity. In MFC suppressive model, FSP-RZ-BPH achieves 84.8% tumor inhibition rate and prolongs the survival of tumor-bearing mice with 57.1% complete response rate. As a preventive tumor vaccine, FSP-RZ-BPH can also significantly delay tumor growth. Overall, the work identifies frameshift MFC neoantigens for the first time and demonstrates the thermosensitive bi-adjuvant hydrogel as an effective strategy to boost bystander anti-tumor responses of frameshift neoantigens.
10.1002/advs.202306889
Thermosensitive Hydrogel with Programmable, Self-Regulated HIF-1α Stabilizer Release for Myocardial Infarction Treatment.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
HIF-1α (hypoxia induced factor-1α), a vital protective signal against hypoxia, has a short lifetime after myocardial infarction (MI). Increasing HIF-1α stability by inhibiting its hydroxylation with prolyl hydroxylases inhibitors such as DPCA (1,4-dihydrophenonthrolin-4-one-3-carboxylic acid) presents positive results. However, the optimal inhibitor administration profile for MI treatment is still unexplored. Here, injectable, thermosensitive hydrogels with programmable DPCA release are designed and synthesized. Hydrogel degradation and slow DPCA release are coupled to form a feedback loop by attaching pendant DPCA to polymer backbone, which serve as additional crosslinking points through π-π and hydrophobic interactions. Pendant carboxyl groups are added to the copolymer to accelerate DPCA release. Burst release in the acute phase for myocardial protection and extended near zero-order release across the inflammatory and fibrotic phases with different rates are achieved. All DPCA-releasing hydrogels upregulate HIF-1α, decrease apoptosis, promote angiogenesis, and stimulate cardiomyocyte proliferation, leading to preserved cardiac function and ventricular geometry. Faster hydrogel degradation induced by faster DPCA release results in a HIF-1α expression eight times of healthy control and better therapeutic effect in MI treatment. This research demonstrates the value of precise regulation of HIF-1α expression in treating MI and other relevant diseases and provides an implantable device-based modulation strategy.
10.1002/advs.202408013
Cabazitaxel-Loaded Thermosensitive Hydrogel System for Suppressed Orthotopic Colorectal Cancer and Liver Metastasis.
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
The treatment of colorectal cancer is always a major challenge in the field of cancer research. The number of estimated new cases of colorectal cancer worldwide in 2020 is 1 148 515, and the estimated number of deaths is 576 858, revealing that mortality accounted for approximately half of the disease incidence. The development of new drugs and strategies for colorectal cancer treatment is urgently needed. Thermosensitive injectable hydrogel PDLLA-PEG-PDLLA (PLEL) loaded with cabazitaxel (CTX) is used to explore its anti-tumor effect on mice with orthotopic colorectal cancer. CTX/PLEL is characterized by a solution state at room temperature and a hydrogel state at physiologic temperature. The excipients MPEG-PCL and PDLLA-PEG-PDLLA have good biocompatibility and biodegradability. The simple material synthesis and preparation process renders this system cost-effective and more conducive to clinical transformation. An orthotopic colorectal cancer model is established by transplantation subcutaneous tumors onto the cecum of mice. According to the results of experiments in vivo, CTX/PLEL significantly inhibits orthotopic colorectal cancer and liver metastasis in mice. The results indicate that CTX/PLEL nanoparticle preparations have high security and excellent anti-tumor effects, and have great application potential in colorectal cancer therapy.
10.1002/advs.202404800
Thermosensitive hydrogel as a sustained release carrier for mesenchymal stem cell-derived extracellular vesicles in the treatment of intrauterine adhesion.
Journal of nanobiotechnology
Intrauterine adhesion (IUA), a prevalent etiology of female infertility, is attributed to endometrial damage. However, conventional therapeutic interventions for IUA are plagued by high recurrence rates. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUCMSC-EVs) demonstrate the promising therapeutic effects on IUA, but the current efficacy of extracellular vesicles (EVs) is hindered by lower retention and bioavailability. In this study, a thermosensitive hydrogel was utilized as a prolonged release carrier to improve the retention and bioavailability of hUCMSC-EVs in IUA treatment. The hydrogel-EVs complex effectively prolonged EVs retention in human endometrial stromal cells and an IUA mouse model. The complex exhibited superior protection against cellular injury, significantly alleviated endometrial damage, inhibited fibrosis, suppressed inflammation, and improved fertility compared to EVs alone. The results indicated that thermosensitive hydrogel enhanced the therapeutic capacity of EVs for IUA by prolonging their retention in the uterine environment. The hydrogel-EVs complex provides a novel strategy for the sustained release of hUCMSC-EVs in the treatment of IUA.
10.1186/s12951-024-02780-2